Triptolide clears Staphylococcus aureus infection by targeting XIAP to induce host apoptosis while preserving gut microbiota homeostasis

ABSTRACT:

Background: Staphylococcus aureus (SA) remains a global health threat due to its increasing drug resistance and intracellular persistence, which compromise the efficacy of conventional antibiotics. Host-directed therapy (HDT) has emerged as a promising alternative by modulating host immunity. With the multi-targeting and immunomodulatory properties, Traditional Chinese Medicine (TCM) monomers represent ideal candidates for HDT. However, their ability to promote host immunity-mediated SA clearance remains largely unexplored.

Purpose: To identify the critical TCM monomer that facilitates the clearance of intracellular SA and methicillin-resistant SA (MRSA), as well as to elucidate its mechanism.

Methods: Fifty-five TCM monomers potentially regulating host immunity were screened to identify a compound promoting intracellular SA/MRSA clearance. The mechanism was investigated using transcriptomics, proteomics, molecular dynamics simulations, and biochemical assays. In vivo holistic regulation was examined in infected mice through lung pathology and multi-omics analysis (transcriptomics, proteomics, metagenomics, and metabolomics).

Results: Triptolide was identified as a potent facilitator of host immunity-mediated intracellular clearance of SA and MRSA, without exerting direct bactericidal effects. Mechanistically, triptolide directly binds to the X-linked inhibitor of apoptosis protein (XIAP), disrupting its interaction with caspases to relieve their inhibition and thereby induce apoptosis. Furthermore, in murine infection models, triptolide treatment reduced bacterial loads and alleviated lung inflammation, while concurrently preserving microbiota homeostasis and improving metabolic function.

Conclusion: This study establishes a proof of concept for triptolide as a HDT candidate against SA and MRSA infections, with a mechanism that not only enhances host apoptosis-mediated pathogen clearance but also preserves host microbiota and metabolic homeostasis.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse-phase, Liquid Chromatography MS - positive - reverse-phase

PROVIDER: MTBLS13930 | MetaboLights | 2026-02-25

REPOSITORIES: MetaboLights